PROJECT SUMMARY/ABSTRACT Heart failure (HF), an epidemic disease, affecting 5.7 million American adults, and the incidence is projected to increase by 46% by 2030. HF is a progressive disease along a continuum from asymptomatic (stage A and B) to symptomatic (stage C and D). Because of the substantial risk of incident HF in patients with asymptomatic LV systolic dysfunction, it is imperative to develop effective interventions at the early stage of HF. Cardiac resynchronization therapy (CRT) is a novel therapy that decreases HF hospitalization and mortality, and improves LV systolic function and HF symptoms. The effectiveness of CRT in patients with mild LV systolic dysfunction?EF of 36%-50% with LBBB?has not been determined. It is unknown whether early resynchronization will prevent LVEF deterioration and reverse ventricular metabolic remodeling. Heterogeneous nature of myocardial metabolism, dyssynchrony and deficient myocardial energy distribution and consumption are hallmarks of HF precipitating myocardial dysfunction. However, the effects of CRT on myocardial energy and substrate metabolism and which metabolic state and pathways facilitate myocardial recovery are unknown. Moreover, the metabolomics signatures of LBBB and metabolic pathways affected in delayed conduction area at the LV lateral wall have not been determined. Furthermore, women may benefit from CRT more than men in terms of improved survival, HF events, and reverse LV remodeling. Yet the metabolic mechanisms underlying favorable CRT outcomes in women have not been elucidated. Metabolomic monitoring of patient body fluids and cardiac-specific coronary sinus blood is of key importance for precision medicine and is included in NIH Roadmap. Accordingly, by analyzing metabolomics patterns in severe and mild HF in the presence of LBBB along with gender and ischemic-non-ischemic HF differences in CRT outcome we will discover metabolic mechanisms which favor the recovery of cardiac function. This study will use stable isotope 18O-based metabolomic technologies and transcardiac metabolic mapping to understand how CRT improves cardiac metabolism and to identify metabolic pathways and novel metabolomic biomarkers that may predict restoration of LV systolic function by CRT. With a cross-over study design, the role of acyl- carnitines, branched chain amino acids and blood phosphometabolite turnover rates will be examined as early biomarkers in relation to LV dysfunction. The study will include three aims. Aim 1: To determine early alteration in metabolic pathways and metabolomics biomarkers in patients with mild HF and LBBB, and their role in the prediction of outcomes of early CRT. Aim 2: To characterize metabolic remodeling pathways in severe ischemic and non-ischemic cardiomyopathy and to determine mechanistic associations with response to CRT. Aim 3: To determine the myocardial metabolomics traits and metabolic mechanisms that underlie a favorable response to CRT in women.